Genetics and Molecular Biology Parkinsonism

遗传学和分子生物学帕金森病

基本信息

批准号：
8134123
负责人：
DENNIS WILLIAM DICKSON
金额：
$ 11.63万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134123
关键词：
Achievement Administrator Advisory Committees Aging Alzheimer&apos s Disease American Americas Animal Model Animals Area Autopsy Award Biochemical Biological Assay Biological Markers Biological Models Book Chapters Boston Brain Calculi Case Study Cell Culture Techniques Cell Line Cell model Cells Cerebrovascular Disorders Chad China Chromosomes, Human, Pair 17 Cities Clinic Clinical Clinical Data Cognition Disorders Collaborations Collection Common Data Element Communities Complement Complication Consensus County Custom Cytopathology DNA Data Data Element Data Set Databases Dementia Development Diagnosis Diagnostic Disease Disease Association Doctor of Philosophy Drug Delivery Systems Drug Formulations Dystonia Education and Outreach Educational Activities Enrollment Eukaryotic Initiation Factor-4G Europe Evaluation Exclusion Criteria FTD with parkinsonism Faculty Family Fellowship Figs - dietary Follow-Up Studies Foundations Foxes Frontotemporal Dementia Funding Future Gene Expression Profile Gene Mutation Generations Genes Genetic Genetic Materials Genetic Screening Genome Genomics Germany Goals Grant Histologic Homologous Gene Hong Kong Human Human Cell Line Hypercapnic respiratory failure Impaired cognition Incidental Discoveries India Industry Institutes Institution Interdisciplinary Study International Internet Ireland Israel Japan Knowledge Korea LRRK2 gene Laboratories Lead Leadership Lewy Bodies Lewy Body Disease Link London Longitudinal Studies MPTP Poisoning Medical Medical Education Medical center Mental Depression Mentors Methods MicroRNAs Minnesota Mission Modeling Molecular Molecular Biology Molecular Diagnosis Molecular Genetics Motor Movement Disorders Multiple System Atrophy Mutation Names National Institute of Neurological Disorders and Stroke Neuroblastoma Neurodegenerative Disorders Neurologic Neurologist Neurology Northern Africa Norway Onset of illness Operon Outcome Paper Parkinson Disease Parkinson&apos s Dementia Parkinsonian Disorders Pathogenesis Pathologic Patient Education Patient Recruitments Patients Peer Review Pennsylvania Pharmacologic Substance Phenotype Phosphotransferases Play Poland Positioning Attribute Postdoctoral Fellow Preclinical Drug Evaluation Predisposition Principal Investigator Process Productivity Progress Reports Progressive Supranuclear Palsy Prospective Studies Protein Binding Domain Proteins Proteomics Publications RNA Interference Recruitment Activity Regulation Reporting Research Research Personnel Research Project Grants Research Proposals Resource Sharing Resources Rest Restless Legs Syndrome Risk Risk Factors Role SNCA gene Saimiri Sampling Scandinavia Scheme Scientist Series Services South America Spain Staging Students Subgroup Sum Support Groups Syndrome System Taiwan Targeted Research Testing Tetanus Helper Peptide Therapeutic Therapeutic Uses Time Toxic effect Training Translating Translational Research Travel Universities Variant Veins Washington Woman Work advanced disease alpha synuclein arm base brain research brain tissue candidate identification clinical material college comparative corticobasal degeneration cost effective cytotoxicity disability disorder risk dynactin early onset gene discovery genetic association genetic risk factor genetic variant genome wide association study genome-wide illness length improved infancy inhibitor/antagonist insight interest kindred leucine-rich repeat kinase 2 medical schools meetings member molecular pathology neuropathology neurosurgery next generation novel outreach population based posters pre-clinical pre-doctoral prevent programs prospective public health relevance skills small molecule small molecule libraries success therapeutic target viral gene delivery web page

项目摘要

DESCRIPTION (provided by applicant): The Udall Center for Excellence in Parkinson Disease Research at the Mayo Clinic is an integrated, multidisciplinary research program of neurologists, neuropsychologists, geneticists, neuropathologists and basic scientists in the study of the "Genetics and Molecular Biology of Parkinsonism." The Center draws upon the clinical strengths of the Mayo Clinic Movement Disorder Section and longitudinal studies of Parkinson disease (PD) and dementia with Lewy bodies (DLB) for the clinical material used in the research projects, as well as strong institutional commitment to PD research. The research proposed is highly synergistic despite the wide range of expertise and scientific background of the members of the Udall team. Each member of the team brings unique knowledge and skill sets to the mission, and together we are greater than the sum of the parts. The work proposed builds upon highly successful and productive cores that have been working together for over a decade. The clinical, genetic and pathologic resources are rivaled by few centers. The Mayo Udall Center is a unique complement to the Udall Center program. Success of our Udall Center has been based upon building successful collaborations and generous sharing of resources and data. This proposal has the overarching goal to better understand Lewy-related PD, which is the most common form of PD. Lewy bodies are also the hallmark of DLB and PD with dementia (PDD). How PDD and DLB relate to each other is unknown, but this non-motor complication of PD is of increasing interest to the Parkinson community. Strengths of our Udall Center are the large collection of multi-incident PD families, a proven track record of success in discovery of PD genes and a large collection of PD, PDD and DLB brains in a well annotated brain bank. The research proposal has three projects and five cores: Project 1. "Identification of genetic risk factors that predict disease onset, susceptibility and progression of PD," (PL: Matthew J. Farrer, PhD); Project 2. "Identification of candidate therapeutics for a-synuclein aggregation and cytotoxicity," (PL: Shu-Hui C. Yen, PhD); Project 3. "Molecular pathology of Lewy-related cognitive dysfunction," (PL: Dennis W. Dickson, MD); Core A. Administrative (CL: Dennis W. Dickson, MD); Core B. Clinical (CL: Zbigniew K. Wszolek, MD); Core C. Genetic (CL: Matthew J. Farrer PhD); Core D. Neuropathology (CL: Dennis W. Dickson MD) and Core E. Education and Outreach (CL: Ryan J. Uitti, MD). PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) is one of the leading causes of neurologic disability. Understanding its cause through genetic studies will lead to animal and cell culture models to develop treatments for PD. With advances in therapies for motor abnormalities in PD, there is increasing interest in understanding non-motor features of PD, including dementia, which is a focus of research. PROJECT 1 Principal Investigator: Matthew J. Farrer, Ph.D. Title: Identification of genetic risk factors that predict disease onset, susceptibility and progression of PD Description (provided by applicant): Work from our past Udall Center application (2004-2009) provides compelling genetic, genomic and biochemical evidence that over-expression of wild-type a-synuclein is a major risk factor for Lewy body disease. Past genetic discovery has immediately improved diagnoses for rare families, and has lead to industry-sponsored translational programs in RNA interference targeting the a-synuclein gene. However, our (PD, PDD, DLB and MSA), and the role of a-synuclein is in its infancy. Project 1 has four aims to addr s these issues: Aim 1 Exonic sequencing of multi-incident family with clinical parkinsonism and autopsy confirmed Lewy body disease. As our preliminary data illustrates, the methods used provide a rapid and cost effective way to identify novel gene mutation(s) in disease. Aim 2 is for comprehensive SNCA genomic capture and re-sequencing of asynucleinopathies, to enable comparative genetic association studies of clinical and pathologic phenotypes across a range of Lewy body disorders. We need to identify the precise variants that influence disease risk, and their molecular mechanism. Work in Aim 3, using a subset of the best characterized samples, will provide complementary data from whole genome transcriptome analysis in a-synucleinopathies. Lastiy, Aim 4 will characterize the role of endogenous miRNA in the regulation of a-synuclein expression. The project could not be accomplished outside of a Center; it rests heavily on resources and expertise offered by Cores B, C and D, and will reciprocally inform research in Projects 2 & 3. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases. We aim to provide a mechanistic understanding of the pathogenesis of Lewy body disorders through gene discovery, and for a-synuclein and its homologues, exploiting advances in next-generation sequencing methods. Public Health Relevance: Novel Parkinson disease (PD) genes identified by this Project in families with PD will provide a window into the cause of PD. Since a-synuclein is the major protein abnormality in PD, a comprehensive study of variability in the gene for a-synuclein will lead to new future therapies for PD.

描述（由申请人提供）：梅奥诊所帕金森氏病研究的UDALL卓越中心是一项综合的，多学科的研究计划，是神经心理学家，神经心理学家，遗传学家，神经病理学家，神经病理学家和基础科学家的“遗传学和帕克森主义遗传学生物学”的研究。该中心借鉴了梅奥临床运动障碍部分的临床优势，以及帕金森病（PD）和痴呆症的纵向研究，其中包括Lewy Bodies（DLB），用于研究项目中使用的临床材料，以及对PD研究的强有力的机构承诺。尽管Udall团队成员的专业知识和科学背景广泛，但提出的研究还是高度协同的。团队的每个成员都为任务带来了独特的知识和技能，我们共同比零件的总和还要多。拟议的作品建立在已经共同努力十多年的非常成功和生产的核心上。临床，遗传和病理资源与几个中心相媲美。 Mayo Udall中心是Udall Center计划的独特补充。我们的Udall中心的成功一直基于建立成功的合作和慷慨的资源和数据共享。该提案的总体目标是更好地了解与Lewy相关的PD，这是PD的最常见形式。路易尸体也是DLB和PD的标志，具有痴呆症（PDD）。 PDD和DLB之间的相互关系是未知的，但是PD的这种非运动并发症引起了帕金森社区的兴趣。我们的Udall中心的优势是大量的多物种PD系列，在发现PD基因的发现成功方面有着可靠的记录，以及大量注释的脑库中的PD，PDD和DLB大脑的大量收集。该研究提案有三个项目和五个核心：项目1。“鉴定预测疾病发作，易感性和PD进展的遗传风险因素”，（PL：MATTHEW J. FARRER，PHD）；项目2。“鉴定A核蛋白聚集和细胞毒性的候选疗法”（PL：Shu-Hui C. Yen，PhD）；项目3。“与Lewy相关的认知功能障碍的分子病理学”（PL：Dennis W. Dickson，MD）；核心A.行政管理（CL：Dennis W. Dickson，马里兰州）；核心B.临床（CL：Zbigniew K. Wszolek，MD）;核心C.遗传（CL：Matthew J. Farrer博士）； Core D.神经病理学（CL：Dennis W. Dickson MD）和Core E. E. E.教育与外展（CL：Ryan J. Uitti，医学博士）。公共卫生相关性：帕金森病（PD）是神经疾病的主要原因之一。通过遗传研究了解其原因将导致动物和细胞培养模型开发PD的治疗方法。随着PD运动异常疗法的进步，人们对理解PD的非运动特征（包括痴呆症）的兴趣越来越大，这是研究的重点。项目1 首席研究员：Matthew J. Farrer博士标题：鉴定预测疾病发作，易感性和PD进展的遗传危险因素描述（由申请人提供）：我们过去的Udall Center应用程序的工作（2004-2009）提供了引人注目的遗传，基因组和生化证据，即野生型A-突触核蛋白的过表达是Lewy身体疾病的主要危险因素。过去的遗传发现立即改善了稀有家庭的诊断，并导致了针对A-核蛋白基因的RNA干扰的行业赞助的转化程序。但是，我们的（PD，PDD，DLB和MSA）以及A-核蛋白的作用仍处于起步阶段。项目1具有四个旨在增加以下问题的目的：目标1具有临床帕金森氏症和尸检的多物种家族的外显子测序证实了刘易体内疾病。正如我们的初步数据所示，所使用的方法为鉴定疾病中新型基因突变提供了一种快速且具有成本效益的方法。 AIM 2是为了全面的SNCA基因组捕获和对异核病态病的重新测试，以实现对一系列路易斯体疾病的临床和病理表型的比较遗传关联研究。我们需要确定影响疾病风险及其分子机制的精确变体。在AIM 3中使用最佳特征样本的子集的工作将提供来自A-突触核酸的整个基因组转录组分析的互补数据。 Lastiy，AIM 4将表征内源miRNA在调节A核蛋白表达中的作用。该项目无法在中心之外完成；它在很大程度上取决于核心B，C和D提供的资源和专业知识，并将在项目2＆3中的研究中相互告知。我们的目标是提供有意义的分子诊断，以重新分类这种异构性疾病。我们旨在通过基因发现以及A-突触核蛋白及其同源物提供对Lewy身体疾病的发病机理的机械理解，从而利用了下一代测序方法的进步。公共卫生相关性：该项目在患有PD的家庭中鉴定出的新型帕金森氏病（PD）基因将为PD原因提供一个窗口。由于A-突触核蛋白是PD的主要蛋白质异常，因此对A-核蛋白基因变异性的全面研究将导致PD的新未来疗法。